The correct regulation of specific target genes in response to incoming neuronal stimuli is essential to healthy cognitive function. NF-kappaB is a transcription factor with well- established and evolutionarily-conserved roles in synaptic plasticity, learning, and memory. In particular, neuronal NF-kappaB is known to be activated by both excitatory neurotransmission and neurotrophic factors, and to regulate the expression of genes that promote the growth and enhance the function of excitatory synapses. However, mechanisms responsible for determining the duration of NF-kappaB-dependent gene expression and for insuring the appropriate stimulus-specific selection of target genes remain unclear. In recent years, high-throughput approaches have highlighted frequently discordant relationships in the profiles of cellular mRNAs and the corresponding proteomes, indicating that additional levels of post-transcriptional control must also be considered in understanding stimulus-dependent programs of gene expression. We recently delineated a pathway by which post-transcriptional specificity in gene expression can be established through both positively and negatively regulating the biogenesis of mature miRNAs to determine whether specific gene transcripts are repressed or undergo enhanced translation. The focus of this proposal is to examine novel molecular mechanisms by which NF-kappaB may exert transcriptional and post-transcriptional control over activity-dependent neuronal gene expression, including both spatial and temporal aspects of this regulation. Our proposed research incorporates approaches ranging from the cellular and molecular level, to behavioral studies. Results from our investigations will reveal previously unknown mechanisms controlling the target specificity and maintenance of changes in gene expression and offer potential new therapeutic targets for the treatment of brain disorders, such as Autism, depression, Trisomy 21, brain cancer and neurodegenerative disease, with known links to dysregulated gene expression.